This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. RNA-dependent RNA polymerases are commonly found in pathogenic viruses from Hepatitis C (HCV) to the common cold (rhinovirus). Structures of RNA-dependent RNA polymerases show a remarkable amount of conservation exhibiting an overall fold with three major domains (palm, fingers and thumb) arranged like a right hand. This strong structural conservation makes viral RNA-dependent RNA polymerases a compelling target for antiviral compounds. Our research focuses on understanding how RNA-dependent RNA polymerases function in order to rationally develop broad acting antiviral compounds.